In early 2019, pembrolizumab was approved for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.1,2
Supporting Efficacy Data
Approval was based on findings in the double-blind EORTC 1325/KEYNOTE-054 trial (ClinicalTrials.gov identifier NCT02362594).3 In the trial, 1,019 patients with completely resected, stage IIIA (> 1 mm lymph node metastasis), IIIB, or IIIC melanoma were randomly assigned to pembrolizumab at 200 mg every 3 weeks (n = 514) or placebo (n = 505) for up to 1 year or until disease recurrence or unacceptable toxicity. Enrollment required complete resection of melanoma with negative margins, lymph node dissection, and completion of radiotherapy, if indicated, within 13 weeks prior to starting treatment. Patients with active autoimmune disease, a medical condition requiring immunosuppression, or mucosal or ocular melanoma were ineligible for the trial. The major efficacy outcome measure was investigator-assessed recurrence-free survival, on Response Evaluation Criteria in Solid Tumors v1.1, in the entire population and in the population with programmed cell death ligand 1 (PD-L1)-positive tumors.
The median age of patients was 54 years (25% ≥ 65 years); all had an Eastern Cooperative Oncology Group performance status of 0 (94%) or 1; 16% had stage IIIA disease, 46% had stage IIIB, 18% had stage IIIC with one to three positive lymph nodes, and 20% had stage IIIC with at least four positive lymph nodes; 50% were BRAF V600 mutation–positive, and 84% had PD-L1–positive disease (tumor proportion score ≥ 1%).
The median recurrence-free survival was not reached in the pembrolizumab group vs 20.4 months in the placebo group (hazard ratio [HR] = 0.57, P < .001). Among patients with PD-L1–positive tumors, the hazard ratio was 0.54 (P < .001). The benefit of pembrolizumab was observed irrespective of tumor PD-L1 expression.
How It Works
Binding of PD-L1 and PD-L2 to the programmed cell death protein 1 (PD-1) receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway may contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose for the adjuvant treatment of adult patients with melanoma is 200 mg of pembrolizumab via intravenous infusion over 30 minutes every 3 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence.
No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 infusion-related reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity.
Pembrolizumab treatment should be withheld for the following, primarily immune-mediated, adverse reactions: grade 2 pneumonitis; grade 2 or 3 colitis; immune-mediated hepatitis in patients with hepatocellular carcinoma and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels at least 5 times the upper limit of normal (ULN) if baseline < 2 times ULN, AST or ALT levels > 3 times baseline if baseline ≥ 2 times ULN, total bilirubin > 2.0 mg/dL if baseline less than 1.5 mg/dL, or total bilirubin > 3.0 mg/dL regardless of baseline level; immune-mediated hepatitis in patients without hepatocellular carcinoma with AST or ALT levels greater than 3 but no more than 5 ULN or total bilirubin greater than 1.5 but no more than 3 times ULN; grade 3 or 4 endocrinopathies; grade 4 hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; grade 2 nephritis; grade 3 skin reactions or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; and any other grade 2 or 3 immune-mediated adverse reaction, based on severity and type. Treatment can be resumed when adverse reactions recover to grade 0 or 1.
Adverse reactions for which pembrolizumab should be permanently discontinued include the following: grade 3 or 4 or recurrent grade 2 pneumonitis; grade 4 colitis; among patients who have immune-related hepatitis with hepatocellular carcinoma, ALT or AST level > 10 times ULN, Child-Pugh score ≥ 9, gastrointestinal bleeding suggestive of portal hypertension, new onset of clinically detectable ascites, or encephalopathy; among patients with immune-mediated hepatitis without hepatocellular carcinoma and without liver metastases, AST or ALT level > 5 times ULN or total bilirubin > 3 times ULN or in patients with liver metastasis and grade 2 AST or ALT level at baseline, an increase in AST or ALT level of 50% or more relative to baseline that persists for at least 1 week; grade 3 or 4 nephritis; grade 4 skin reactions or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; other immune-mediated reactions of grade 3 based on the severity and type of reaction or grade 4 reactions; recurrent immune-mediated adverse reactions including recurrent grade 2 pneumonitis and other recurrent grade 3 or 4 events; inability to taper corticosteroid treatment; and persistent grade 2 or 3 adverse reactions (excluding endocrinopathy).
The most common adverse events reported in at least 20% of patients who received pembrolizumab as a single agent in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
In the EORTC 1325/KEYNOTE-054 trial, the most common adverse events of any grade in the pembrolizumab group that occurred at the same or higher incidence than in the placebo group were diarrhea (28% vs 26%), pruritus (19% vs 12%), nausea (17% vs 15%), arthralgia (16% vs 14%), and hypothyroidism (15% vs 2.8%). The most common grade 3 or 4 adverse events included diarrhea and arthralgia (both 1.2%). Grade 3 or 4 laboratory abnormalities included increased ALT (2.4%) and increased AST (1.8%) levels.
Serious adverse events occurred in 25% of patients who received pembrolizumab. Adverse events led to interruption of pembrolizumab in 19% of patients and to treatment discontinuation in 14%, with the most common causes of treatment discontinuation being pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Two patients who received pembrolizumab died of causes other than disease progression, including drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure.
Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis; immune-mediated colitis; immune-mediated hepatitis; immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes); immune-mediated nephritis; immune-mediated skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis; other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab. ■
1. U.S. Food and Drug Administration: FDA approves pembrolizumab for adjuvant treatment of melanoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm631565.htm. Accessed December 10, 2019.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co, Inc, February 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s040lbl.pdf. Accessed December 10, 2019.
3. Eggermont AMM, Blank CU, Mandala M, et al: Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789-1801, 2018.